PROJECT SUMMARY Both the innate and acquired immunity play important roles on systemic inflammation and pathogenesis of malaria as well as host resistance to Plasmodium infection. When patients are symptomatic with disease, they generally seek curative therapy, thus interrupting potential transmission. In contrast, individuals with asymptomatic disease, at least in theory, remain as reservoirs of disease. In this project, we will address questions related to the innate and acquired immune responses that are relevant to understanding the emergence and persistence of asymptomatic malaria individuals. Our previous epidemiological studies in the Amazon suggest that multiple malaria infections result in substantial immunity, which is able to control, but not eliminate malaria infection. In contrast to the acutely ill patients, the malaria immune individuals do not display systemic inflammation and signs of disease. Our overall hypothesis is that innate immune cells from individuals with low and persistent parasitemia, become hyporesponsive to Plasmodium stimulation preventing systemic inflammation, but at the same time being unable to promote an acquired immune response that is efficient in eliminating infection. We believe that despite the low levels of parasitemia, and the predicted low rate of transmission per mosquito bite, such patients continue to be infective over long periods of time and hence represent a silent barrier to efforts to eliminate malaria in the Amazon. In this project, we propose to compare the innate and acquire immune responses elicited by Plasmodium infection in acutely ill and asymptomatic patients, and to define mechanisms that are potentially involved in modulating the systemic inflammation and preventing parasite elimination in asymptomatic malaria patients. Our first aim is to compare the inflammatory response and responsiveness of innate immune cells from clinically ill and asymptomatic malaria patients. In the second aim we will compare the development of humoral and cellular acquired immune responses as well as immunoregulatory mechanisms that may influence hyper and hypo innate immune responses in patients undergoing acute versus asymptomatic P. vivax or P. falciparum infection. Finally, in Aim 3 we will investigate in longitudinal studies, various immunological, parasitological and clinical parameters in patients with recurrent infection. We intend to validate the biomarkers defined in Aims 1 and 2, and to interrogate whether asymptomatic patients are prone to develop no diseases in recurrent infections. We will also search for immunological correlates of infectivity of symptomatic and asymptomatic P. vivax parasitemics for colonized An. darlingi mosquitoes. Outcomes of these experiments will identify innate immune biomarkers as well as B and T cell responses that are predictive of disease outcome and mosquito transmission. If successful, our studies will provide important information for monitoring silent infection in infective asymptomatic individuals and potentially new insights to further control malaria transmission in hypo- endemic areas.